This grant is based on the hypothesis that airway epithelial cells participate in and reflect the molecular events that determine the genesis and phenotypic characteristics of COPD in smokers. We propose that measuring global patterns of gene expression in airway epithelial cells will provide important new information about initiation and progression of the biologic processes that lead to COPD. In addition, this information should, when correlated with clinical and physiologic data, provide new ways of classifying COPD and may define, at a molecular level, more rational approaches to therapy. We plan to use an established lung tissue bank, and an active COPD cohort study, together with new patient recruits (all at St. Elizabeth's Medical Center), to examine (at Boston University School of Medicine Pulmonary Center) expression array patterns of human genes in resected lung tissue and to compare lung tissue and airway epithelial gene expression in airway cells obtained at bronchoscopy. Bioinformatic tools will be used to develop class prediction models to link gene expression to clinical and physiologic profiles, thus identifying genes that distinguish different forms of cigarette-induced airway damage, different pathways of COPD evolution, and different approaches to prognosis and perhaps treatment of COPD. The "Innovation Research Program" aspects of the studies we propose, fit the stated goals of this program in that they: 1) utilize and expand existing data sets and specimen collections; 2) establish new scientific and institutional collaborations; and 3) apply novel molecular approaches to understanding the genesis and classification of COPD in smokers. We believe that these studies will lead to "class prediction" models that can subsequently be tested using custom-designed (rather than discovery arrays) in larger populations of smokers with and without COPD.